A fracture which fails to heal for a year and a half to three years is termed a fracture nonunion. It is characterized by pain, inability to bear weight and morbidity. Causes of fracture nonunions are thought to include too large a gap between the bone ends, micromotion present during the healing period, and/or lack of adequate vascularization.
Nonunion of long bone fractures is a serious complication of fracture healing, and usually results in long-term disability. Although nonunion develops in only one to five percent of all diaphyseal fractures, it is estimated that 100,000 nonunions of long bones occur in the United States annually (Calandruccio, R., ed. "Musculoskeletal system research: Current and future research needs," (ed 1981) American Academy of Orthopaedic Surgeons, Chicago). Failure of fracture healing results in pain, instability, and associated loss of function of the involved limb. In addition, because a significant number of fractures occur in young, productive individuals, the degree of disability produced by this problem is substantial.
During normal fracture healing, periosteal new bone is formed, and undifferentiated mesenchymal cells form fracture callus, proliferate, and differentiate into chondrocytes. These cells calcify their cartilaginous matrix, which then undergoes vascular invasion, resorption, and formation of bone on the scaffold of calcified cartilage. (Brand, R. A. and Rubin, C. T. (1990), "Fracture Healing," In Surgery of the Musculoskeletal System (C. McC. Evarts, Ed.) vol. 1 pp. 93-114, New York, Churchill Livingstone.) When there is a nonunion, however, periosteal new bone fails to bridge the defect, and the connective tissue that joins the fragments of bone develops into fibrocartilage. The matrix does not calcify, and osseous union and healing are not achieved. (Heckman, J. D., et al. (1991), "The Use of Bone Morphogenetic Protein in the Treatment of Non-Union in a Canine Model," J. Bone and Joint Surg. 73-A:750-764; Santos Neto, F. L. and Volpon, J. B. (1984), "Experimental Nonunion in Dogs," Clin Orthop. 187:260-271.)
The standard clinical approach at this time to achieving healing of nonunions involves a variety of surgical procedures designed to stabilize the nonunion and simultaneously stimulate new bone formation (Boyd, H. B., "Symposium: Treatment of ununited fractures of the long bones," J. Bone and Joint Surgery 1965 47A:167-168; Nicoll, E. A., "Fractures of the tibial shaft: survey of 705 cases, " J Bone and Joint Surgery 1964 46B:373-387). These treatment modalities generally incorporate the techniques of internal fixation combined with autogenous bone grafting and have a success rate varying from 85 to 95 percent (Edmonson, A. S. and Crenshaw, A. H., ed. Campbell's Operative Orthopaedics, (1987) 7th ed., CV Mosby, St. Louis). Iliac crest autograft has been shown to be an effective graft material (See, for example, Goldstrohm et al., J. Trauma, 24:50-58, 1984), but the supply is limited, requiring, in some cases of segmental defect repair, multiple procedures to obtain sufficient material.
Significant complications are associated with the harvest of autologous bone graft material (Younger, E. M. and Chapman, M. W., "Morbidity at bone graft donor sites," J. Orthopaedic Trauma (1989) 3:192-195). The removal of cancellous graft can create additional surgical trauma, increase the potential for infection, and, by lengthening the operating time, increase the risk. One alternative may be to use exogenous bone growth factors to stimulate bone growth at nonunion sites (Cornell, C. N. and Lane, J. M., "Newest factors in fracture healing," Clin Orthopaedic Relates Res. (1992) 227:297-311).
These disadvantages have spurred investigations of alternative bone repair materials. Bioceramics of calcium phosphate have attracted widespread attention because of their biocompatibility and chemical similarity to the bone matrix, which results in direct bonding to bone without intervening fibrous tissue (Osborn et al., Biomaterials, Winter, Gibbons, Plenk (eds.) 1980). However, they tend to be brittle, difficult to shape, and remain in the repair for time periods greater than 12 months (Holmes et al., Clin. Orthop. Rel. Res. (1984) 188:252-262) .
Tricalcium phosphate disks have been used for treatment of craniotomy wounds in rabbits. (Hollinger, J. O., et al. (1989), "An evaluation of two configurations of tricalcium phosphate for treating craniotomies," J. Biomedical Materials Research 23:17-29.) Polylactic acid both with and without canine bone morphogenic protein was molded into the shape of nonunion defects created in dogs to create friable implants for evaluation. Modest healing was observed with the implant alone; bridging of the defect was observed with the implant containing the canine bone morphogenic protein. (Heckman, J. D., et al. (1991), "The Use of Bone Morphogenetic Protein in the Treatment of Non-Union in a Canine Model," J. Bone and Joint Surg 73A:750-764.)
Metal internal fracture fixation plates, produced for example from stainless steel, frequently have an elastic modulus greater than ten times that of bone. Although plate rigidity is an advantage for achieving primary osseous union, it tends to inhibit external callus formation, which is considered a good method for restoring the strength of the broken bone to its original level (Kelley et al., Advances in Biomedical Polymers, Gebelein, C. G. (ed.), Plenum Press, New York, 1987). Active remodeling of the bone after fracture healing may also be compromised unless the rigid plate is removed, often resulting in stress protection and, consequently, osteoporosis and atrophy beneath the plate.
The potential advantages of internal fixation devices produced from biodegradable polymers have long been recognized. Primary bony union and callus formation can be achieved by an adequately stiff and strong plate. Load transfer to the healing bone and bone remodeling may be promoted by a gradually reducing plate stiffness as biodegradation proceeds. Finally, the need for plate removal is eliminated by resorption of the device.
Kulkarni et al., Arch. Surg., 93:839-43 (1966) describe the production of poly(DL-lactic acid) pins for reduction of mandibular fractures in dogs. Getter et al., J. Oral Surg., 30:344-48 (1972), describe the use of high molecular weight PLA plates to treat mandibular fractures in dogs. Leenslag et al., Biomaterials, 8:70-73 (1987), disclose treatment of fractured zygoma in 10 patients using high molecular weight PLA plates. Such polymers, however, tend to be absorbed very slowly. Bostman et al., J. Bone and Joint Surgery, 69-B, No. 4 (1987), describe the use of high strength, fast resorbing, self-reinforced PLA/PGA rods for routine treatment of patients with displaced malleolar fractures.
The poly alpha-hydroxy acids are a class of synthetic aliphatic polyesters, the main polymers of which are polylactide (alternatively referred to as polylactic acid) and polyglycolide (alternatively referred to as polyglycolic acid). These materials have been investigated for use in a variety of implant systems for soft tissue and osseous repair in medicine and dentistry, since they tend to exhibit very good biocompatibility and are biodegradable in vivo. The need to remove the device after tissue repair can thereby be reduced or eliminated. The alpha-hydroxy acids are also being investigated for production of controlled release rate delivery systems for bioactive materials, such as pharmaceuticals.
The ability to vary the biodegradation rate of synthetic alpha-polyesters by material selection, copolymerization, control of molecular weight, crystallinity and morphology makes them attractive for bone repair. Resorption rate can be varied from two weeks to over a year, for example, so that implant resorption may be tuned to bone repair rates (Hollinger et al., Clin. Orthop. Rel. Res., 207:290-305, 1986) PLA/PGA copolymers have been used alone (Hollinger, J. Biomed. Mater. Res., 17:71-82, 1983) and as binders for bioceramics (Haggish et al., Biomaterials, 7:183-87, 1986) and decalcified allogeneic bone (Schmitz et al., Clin. Orthop. Rel. Res., 237:245-55, 1988) to produce bone fillers for repairing bony deficiencies in animals.
Such polymers can also function as delivery systems for growth factor(s) as they biodegrade. U.S. Pat. No. 4,578,384 discloses a protein-acidic phospholipid addition to PLA/PGA copolymer which is reported to increase bone healing rates in rat tibias relative to the copolymer. PLA could, in itself, play a dual role of bone filler and bone growth factor. Hollinger, J. Biomed. Mater. Res., 17:71-82 (1983), reported that a 50:50 copolymer of poly(L-lactic co-glycolide) increased the rate of early osseous healing when implanted in rat tibial defects. Thus, it appears that the degradation characteristics of these linear aliphatic polyesters may play a role in the stimulation of hard and soft tissue growth, which increases the attraction of using PLA and PGA for repairing soft or hard tissue.
The lactide/glycolide polymers and copolymers tend to demonstrate an easily characterized and controllable degradation rate and tend to be nontoxic, which is advantageous for manufacture of controlled release rate delivery systems for a wide variety of bioactive materials, such as pharmaceuticals. U.S. Pat. No. 4,563,489 discloses production of a biodegradable polymer delivery system for bone morphogenetic protein based on a poly(lactide co-glycolide) copolymer. Development of suitable delivery methods is important for such therapeutic proteins since they are readily absorbed by the body. Schakenraad et al., Biomaterials, 9:116-20 (1988), describe the development of a biodegradable hollow fiber of poly(L-lactide) for controlled release of contraceptive hormone.
U.S. Pat. No. 4,719,245, and related U.S. Pat. No. 4,800,219 disclose compositions wherein segments of poly(R-lactide) interlock or interact with segments of poly(S-lactide), producing a crystalline phase having a melting point higher than that of either component. Processes are described for preparing the above compositions, e.g., by mixing and combining the previously prepared polymeric components in a suitable solvent or in the molten state and processes for preparing gels and porous structures of the compositions. The patent discloses spontaneous gel formation from solutions of blended polylactide enantiomers on stirring. It is described that porous structures are produced from gels of the composition by a process comprising solvent exchange and evaporation.
U.S. Pat. No. 4,883,666 describes discs 3 mm in diameter made by solvent casting of ethylene vinyl acetate slabs containing dopamine coated with ethylene vinyl acetate for linear release of L-dopa for treatment of disorders of the nervous system. The reference states that polylactic acid and polyglycolic acid can be used as carriers, however, methods for achieving the required linear release are not disclosed. U.S. Pat. No. 5,330,768 describes the use of block copolymers of polyethylene oxide and polypropylene oxide in polylactic acid and polyglycolic acid polymer formulations for control of drug release rate. This patent discloses that fast release of an initial burst of additive may be controlled by slow removal of organic solvent from the polymer at low temperatures and by adding the block copolymer. No initial burst of drug release is reported in U.S. Pat. No. 5,336,505 which employs bioerodible ortho ester polymers for implants and other pharmaceutical preparations.
U.S. Pat. No. 4,637,931 discloses production of a bone repair material consisting of decalcified freeze-dried bone (DFDB) and biodegradable biocompatible copolymer, namely poly[L(-) lactide co-glycolide] copolymer, which is described as being used for improving and accelerating the healing of osseous tissue.
U.S. Pat. No. 4,578,384 discloses a material, consisting of a combination of a proteolipid and a biodegradable, biocompatible copolymer which is stated to facilitate improved healing of osseous wounds when implanted at the site of the broken tissue.
The methods disclosed in U.S. Pat. Nos. 4,637,931 and 4,578,384 for producing biodegradable bone repair materials from polymer solutions generally comprise the stages of polymer dissolution, polymer precipitation in a nonsolvent, partial drying of the precipitate and compaction of wet precipitate in a mold, followed by heating/drying to produce the finished implant.
U.S. Pat. No. 4,563,489 discloses a biodegradable PLA polymer delivery system for bone morphogenetic protein (BMP) to induce formation of new bone in viable tissue. The delivery composition described is substantially pure BMP in combination with a biodegradable PLA polymer, prepared by admixing the BMP with the biodegradable polymer. The composition is implanted in viable tissue where the BMP is slowly released and induces formation of new bone.
The method for preparing the implant material of U.S. Pat. No. 4,563,489 generally comprises (1) dissolving the physiologically acceptable biodegradable polymer in a solvent such as ethanol, acetone or chloroform, (2) admixing the polymer solution with BMP to form a dispersion of BMP in the polymer solution, and (3) precipitating the composite by adding a second solvent which causes precipitation of the polymer or lyophilizing the dispersion or otherwise treating the dispersion to remove it from solvent and form the BMP-PLA composite. After composite formation, it is filtered, pressed or otherwise processed to remove the solvent, and the resulting composite solid is formed into the desired shape for implantation. Other additives may be included, e.g., antibiotics, prosthesis devices, radio-opacifying agents.
The delivery compositions of U.S. Pat. No. 4,563,489 have relatively small masses and are used in relatively thin layers (i.e., in the range of 1 mm to 2 mm in thickness). In one example, implants are described as being shaped by pressing the wet BMP-PLA precipitate in a mold to express the second solvent prior to drying. Wet (precipitated) composite was also shaped using glass molds to produce flakes, rods, films or plates. The patent also mentions that in preferred embodiments the BMP/biodegradable polymer delivery composition is formed into a dough, rod, film, flake or otherwise shaped as desired. The patent further mentions that the BMP/PLA composition, while still dispersed or dissolved in solvent, may be formed into small pellets, flakes, platelets, etc., by casting in molds and allowed to dry or harden.
U.S. Pat. No. 4,645,503 discloses production of a moldable bone implant material containing approximately 65-95% hard filler particles and a binder composed of approximately 35-50% of a biocompatible, biodegradable thermoplastic polymer which has fluidic flow properties at a selected temperature at or below about 60.degree. C. Variation in biodegradation rate via the usual routes for biodegradable polymers is described, namely (1) adjustment of molecular weight, (2) substitution of the polymer subunit (copolymerization), (3) blending with a slower degrading polymer, or (4) increasing the surface area for hydrolysis by varying the proportion of binder and particles to provide voids or pores in the material.
All publications and patents referred to herein are hereby incorporated by reference in their entirety.